Method of using 6-substituted amino phenyl-2,3,5,6-tetrahydro-{8 2,1-B{9 thiazoles

ABSTRACT

The preparation of dl and l compounds of the type 6-(mono and di-substituted phenyl)-5,6-dihydro or 2,3,5,6tetrahydroimidazo(2,1-b)thiazoles and the pharmaceutically acceptable salts thereof, is described. The use of said compounds for treating helminthiasis in warm-blooded animals is also described.

United States Patent Spicer et al.

METHOD OF USING G-SUBSTITUTED AMINO PHENYL-ZJ,5,6-TETRAHYDRO-[2.1-3] THIAZOLES Inventors: Larry Dean Spicer, Princeton; John James "and, Trenton. both of NJ.

Assignee: American Cyanamid Company,

Stamford, Conn.

Filed: Nov. I6, 1973 Appl. No.: 4l6,464

Related US. Application Data Division of Ser. Nov 289,0l6, Sept. [4, 1972, which is a continuation-in-part of Ser. No. l74,939, Aug. 25, 197], abandoned, which is a continuation-in-part of Ser. No. 22.701. March 25, I970, Patv No. 3.673205.

U.S. Cl. 424/270; 424/248; 424/267 [451 Aug. 12, 1975 Int. Cl. A61K 27/00 Field of Search 424/270 References Cited OTHER PUBLICATIONS Chem. Abst.. 8th Collective Index, Vol. 66-75, (1967-4971), p. 15653 S.

Primary Examiner-Stanley J. Friedman Attorney, Agent, or Firrn-Ernest Y. Miller l3 Claims, N0 Drawings METHOD OF USING 6-SUBSTITUTED AMINO PI-IENYL-Z.3,5,6-TETRAHYDRO-(2.l-b) THIAZOLES This application is a division of application Ser. No.

289,0l6, filed Sept. 14, 1972, which is acontinuationtaken together represents piperidino, pyrrolidino. or

in-part of our application Ser. No. 174,939, filed Aug. 25, I971, now abandoned, which is a continuation-inpart of application Ser. No. 22,701, filed Mar. 25, 1970, now U.S. Pat. No. 3,673,205.

BACKGROUND OF THE INVENTION A number of 6-substituted-imidazo[2,l-blthiazoles are generically disclosed by Raeymakers et al. in their U.S. Pat. Nos. 3,274,209, issued Sept. 20, I966 and 3,364,112, issued Jan. 16, 1968. Use of these compounds as anthelmintic agents is also suggested and data for several compounds are described. The compounds actually exemplified, however, have their limitations. This is especially evident when such compounds are employed for control of whipworms, particularly in Canidae. While both the optically dl-6-phenyl- 2,3,5 ,6-tetrahydroimidazo[2, l -b]thiazole of Raeymakers et al. and the optically active l-6-phenyl-2,3,5,6- tetrahydroimidazo[2,l-b]thiazole of Bullock, U.S. Pat. 3,463,786, issued Aug. 26, 1969, are highly effective against most helminths, they are not sufficiently active against whipworms, especially in dogs, to permit the use of a dosage level which will effectively control whipworm infestations while maintaining a margin of safety considered to be desirable or acceptable.

DESCRIPTION OF THE INVENTION Surprisingly, we have now found that effective and safe whipworm control in warm-blooded animals can be obtained with a group of dl and l compounds of the formula below and their pharmaceutically acceptable salts.

R and R are selected from the group consisting of hydrogen, alkyl (f -C alkenyl C -C cycloalkyl C -C hydroxyloweralkyl, loweralkanoyloxyloweralkyl, loweralkoxyloweralkyl, benzyl, substituted benzyl, phenylethyl, substituted phenylethyl, monoand dinitrophenyl, 2- and 4-pyridyl, 2- and 4-pyrimidinyl, 2- thiazolyl, pyridylmethyl, furfuryl, tetrahydrofurfuryl, R,=,C(O) wherein R is selected from the group consisting of hydrogen, alkyl C C alkenyl C C cycloalkyl C -C haloalkyl C,C,,, aminoalky] C -C monoloweralkylaminoloweralkyl, diloweralkylaminoloweralkyl, piperidinoloweralkyl, pyrrolidinoloweralkyl, morpholinoloweralkyl, loweralkoxyloweralkyl, phenyl, substituted phenyl, furyl, tetrahydrofuryl, naphthyl, alkoxy C C amino, monoloweralkylamino, diloweralkylamino, piperidino, pyrrolidino, and morpholino; and where morpholino ring or the group (loweralkyl)-;NCH=N; and R and R are selected from the group consisting of hydrogen, halogen, and nitro; it being understood that the term substituted is intended to cover monohalo, dihalo, trihalo, mononitro, dinitro, monoloweralkyl, diloweralkyl, triloweralkyl, monoloweralkoxy, diloweralkoxy, and triloweralkoxy, and the term halogen" or halo" refers to fluoro, chloro. bromo, and iodo; with the proviso that when R; and R are both hydrogen not more than one member from the group R and R, can be hydrogen,--=is a single or double bond. The term lower is intended to include those groups having l to 4 carbon atoms.

The preferred compounds of the present invention may be further categorized as follows: l) compounds of the above formula wherein R and R are as described above and R and R are each hydrogen; (2) compounds of the above formula wherein R, and R are as described above, one of R and R is hydrogen and the other is halogen or nitro and is attached to the carbon in either the 4-position or the 6-position of the ring; and (3) compounds of the above formula wherein R and R are both hydrogen or where one of R and R is a halogen or nitro group attached to the carbon at the 4- or 6position of the ring and represents lower alkylamino, diloweralkylamino, formylamino, formyl loweralkylamino, lower alkoxy carbonylamino, lower alkylamino carbonylamino, benzoyl or lower alkanoyl amino.

In referring to the highly anthelmintically active optical isomers dislosed herein we use the designation 1. Since this designation refers to the sign of optical rotation, and is not as definitive a symbol as those which refer to absolute configurations of molecules, it is to be understood that l as used herein describes compounds with the same absolute configuration as the highly anthelmintically active optical isomer of 6-phenyl- 2,3,5,6-tetrahydroimidazo[2,l-b]thiazole, which is described by Raeymaekers et al., Tetrahedron Letters, 1467 1967), as having the L or S configuration.

Broadly speaking, the compounds of this invention can be prepared by a process for the preparation of a compound or the pharmaceutically acceptable acid salt thereof having the formula:

wherein R, and R are selected from the group consisting of hydrogen, alkyl C C alkenyl C C, cycloalkyl C -C hydroxyloweralkyl, loweralkanoyloxyloweralkyl, loweralkoxyloweralkyl, benzyl. substituted benzyl, phenylethyl, substituted phenylethyl, monoand dinitrophenyl, 2- and 4-pyridyl, 2 and 4-pyrimidinyl, 2- thiazolyl, pyridylmethyl, furfuryl. tetrahydrofurfuryl. R C(O) wherein R is selected from the group consisting of hydrogen, alkyl C -C alkenyl C- C cycloalkyl C C haloalkyl C C aminoalkyl C C monolowen alkylaminoloweralkyl, diloweralkylaminoloweralkyl. piperidinoloweralkyl, pyrrolidinoloweralkyl. morpholinoloweralkyl, loweralkoxyloweralkyl, phenyl, substituted phenyl, furyl, tetrahydrofuryl, naphthyl, alkoxy C C, amino, monoloweralkylamino, diloweralkylamino. piperidino, pyrrolidino, and morpholino, and where taken together may represent piperidino, pyrrolidino, or morpholino ring or the group (loweralky1) NCH- =N; and R and R are selected from the group consisting of hydrogen, halogen, and nitro, the term substituted covers monohalo, dihalo, trihalo, mononitro, dinitro, monoloweralkyl, diloweralky], triloweralkyl, monoloweralkoxy, diloweralkoxy, and triloweralkoxy; and the term halogen covers fluoro, chloro, bromo, and iodo; with the proviso that when R; and R. are both hydrogen not more than one member from the group R and R can be hydrogen, and represents single or double bond, comprising reacting a compound of the formula:

N-CHz-CH where R,, R R R; are as described above and R is hydrogen or loweralkanoyl, preferably acetyl and X is an anion, with (a) concentration sulfuric acid and treating the thus formed product with a base, preferably an alkali metal hydroxide or ammonium hydroxide, or (b) thionyl chloride at a temperature of from 40C. to 75C. and treating the reaction product with acetic anhydride at 50C. to 140C, removing excess loweralkanoyl anhydride from the thus formed product, treating the product with strong mineral acid and then treating the acid solution with an alkali metal hydroxide or ammonium hydroxide to yield the desired product.

In accordance with the present invention, an appro priate anilide such as 3'-acetylacetanilidc, 3' acetyllbrmanilidc, 3'-acetylpropionanilide or 3- acetylbutyranilidc is dissolved in an inert solvent such as methylene chloride, chloroform, carbon tetrachlo ride or the like, and treated with bromine, chlorine, or the like, to form the corresponding 3'-chloro or 3'- bromoacetylacetanilide, form-anilide. propionanilide,

or butyranilide shown as formula (1) on the flow dia' gram hereinafter.

Treatment of the formula (I) anilide with an equimolar amount of 2-aminothiazole or 2-amino-2-thiazoline in an inert solvent such as methylene chloride, chloroform. acetone, ethyl acetate or the like, at a temperature between about 20C. and C., yields the 3'-[(2- imino-4-thiazolin-3-y1)acetyl]acetanilide, formanilide, propionanilide or butyranilide, hydrochloride or hydrobromide salt of formula (11 This salt is treated with at least the theoretical amount of an alkali metal borohydride in the presence of a lower alcohol such as methano], ethanol, butanol, isopropanol, water-lower alcohol mixture or the like and then acidified with an organic or hydrohalide mineral acid to form the hydroxyethyl acetanilide hydrohalide of formula (IVB). We have also found that the formula ([1) iminothiazolinyl anilide hydrohalide can be treated with acetic anhydride in the presence of an inert solvent such as acetic acid and an alkali metal acetate at a temperature between about 50C. and C. to obtain the formula (Ill) 2- acetylimino thiazolinyl anilide readily converted to the thiazolinyl anilide formula (lVA) by reaction with an alkali metal borohydride. The reaction conditions used are similar to the alkalimetal borohydride treatment of the formula (11) compounds.

Cyclization of the thiazolinyl anilide (IVA) and hy drohalide (formula IVB) can be carried out by reacting said compounds with thionyl chloride at a temperature between 40C. and 75C. and treating the reaction product with acetic anhydride at about 50C. to 140C. The reaction product is then dissolved in hydrochloric acid and made basic with ammonium hydroxide or an alkali metal hydroxide to yield the dihydroimidazo thiazolyl acetanilide shown as formula (V). If this product is then treated with perchloric acid, the perchlorate salt of formula (V) is obtained.

Cyclization of the formula (IV) compounds can also be achieved by reaction with concentrated sulfuric acid. The free base is obtained by treatment of the reaction product with strong base such as ammonium hydroxide or alkali metal hydroxide. This reaction yields both the dihydro and the tetrahydroimidazo thiazolyl acetanilide free bases of formula (V). Treatment of the imidazo thiazolyl acetanilide of formula (V) with hydrochloric or hydrobromic acid yields the aminophenyl imidazothiazole dihydrohalide of formula (Vll).

Advantageously, the formula (Vll) compound can also be prepared from 2,3,5,6-tetrahydro6-(m-nitrophcnyl)imidazo[2,1-b]-thiazole hydrochloride (Vl) by reacting such compound with stannous chloride and hydrochloric acid at higher temperature, for example, between about 60 and 100C. The resulting product is then neutralized with an alkali metal hydroxide separated from the tin salts and the reduced product treated with an alcoholic hydrohalide.

The m-aminophenyl compound of formula (Vll) as the free base can be converted to the corresponding form-anilide of formula (Vlll), by reaction with formic acid. The reaction may be carried out in the presence of an inert solvent such as toluene. or in formic acid alone. The reaction is generally carried out at a temperature between 50C. and C. but 75C. to 100C is usually a preferred range.

The formanilide (VIII) is then treated with lithium aluminum hydride in the presence of an inert solvent such as tctrahydrofuran at a temperature between about 25C. and 75C. and preferably 40C. to 50C. The m-methylaminophenyl imidazothiazole of formula (lX) is then obtained.

QL TJ |-(1-( m-aminophenyl )-2,3.5 .6-tctrahydruimidazol 2. 1-11 lthiazolc dihyd rochloridc and d-olm-uminophcnyl )-2 3.ifi-tctrahydroimiduzol 2. l

the present invention. This reaction is illustrated as follows:

N s El I S Cl N0 1-6-1mnilrophcnyl)-2.3.5 .640trahydroimidazol 2 l -b lthiazolc hydrochloride and d-(w-(mmitrophcnyl ]2 3.5.o-lctrahydroimiduzol 2. l blthiazolc hydrochloride.

VII

hlthiazole dihydrochlorider The reactions described above can be illustrated by the following:

s iicocua R. gfl gog .0 n. I 3 S H g i? KOOOCH; )1 o ti-cii -c i H x -CH2-G- B111;

1. M nn. 2mm; 2. H x N na,

1. socl /nr m S 0 I 4 L 3,899,583 7 8 For the preparation of compounds where R is hydroshown above and are illustrated in Flow Diagram II, as gen and R is COR- process steps are similar to those fnlluwsi FLOW DIAGRAM I I COCK; 012 or are a x l HC0R BOOK;

"A B5 CH3 X =-Br a s ucocns cnacom 5 NH F Y KOCOCH [g 9 '--N-CH --c E gcii cm o wcnrc x NHCORs IIIA R5 H CH3 IIA R5 CH3 X Br 113 B5 CH;

X Br

1. N&BH .1-:

1. NaBH L 2. I-Dfi s 3 (Nll R4 L u-cn ri'n 0H mucou .nx

IVA n cocii 1. socl lnm' 1. H 50.

5 3 2. AC O 195 2 Zero 3 1 IVB R0 H 8 N Y x BOOK.

YE, I5 L CH3 X perchloric acid E R5 CH3 X zero FLOW DIAGRAM II continued v R 5% L l I l --e N NlhR Compounda VII s N U NHCHO 1. LiAlH VIIIA R4 s n [g i .eux IXA x NHCH wherein R is hydrogen or acetyl, R is hydrogen or lower alkyl (C,C; X is perchlorate chlorine or bromine and -is a single or double bond.

The compounds at the present invention can also be prepared using as starting material 64maminophenyl )-2.3.5,o-tetrahydroimidazol 2 l blthiazole. The dl-(macylaminophenyl)2,3.5 6- tctrahydro[2.1b]thiazoles can be resolved into the d and I isomers with the optically active dibenzoyltartaric acids. The acetamido, isobutryamide, and benzamido derivatives are especially easily resolved with this reagent. The amide group is then removed by acid hydrolysis. The l-isomer of the m-aminophenyl compound is almost twice as active as the dl compound and can be used in the same manner as an intermediate. The maminophenyl compound can be acylated or alkylated to produce the desired compounds. The reactions can be carried out at a temperature of from 20C. to 120C. usually in the presence of a solvent.

The alkylamino compounds are best prepared by reductive alkylation procedures as illustrated by the equation below:

l l N N 11 C R Reduction c... 17H C R' R wherein R and R are hydrogen, alkyl or aryl.

This method is especially useful for aldehyde carbonyl compounds since the reduction proceeds very rapidly and in high yield. Furthermore, there is no alkylation at the 7-position of the imidazo[2,1-b]thiazole ring system. The preferred reagent for preforming the reduction is sodium cyanoborohydride although other reagents can be used under certain conditions.

These products are also available by direct alkylation of the amine compounds (Vll) with alkyl halides. This method is useful for secondary halides since they do not alkylate the 7-position readily.

The compounnds of the present invention are useful as anthelmintic agents effective for treating helminthiasis in warm-blooded animals.

They are highly effective at very low dosage levels, for example. at from 1 to about 10 mg./kg. of body weight and preferably are utilized at dose levels from 1.5 to 5.0 mg./kg. of body weight of warm-blooded animal. lmportantly, they are effective for removing all of the important gastrointestinal nematodes; namely, ascarids, hookworm, whipworms and tapeworms. They have the advantage over their known relatives of being highly effective against whipworms, a helminth heretofore extremely difficult to control. They may be used for treatment of helminthiasis in laboratory, farm and domestic animals as well as wild animals held in captivity and are particularly useful in the treatment of helminthiasis in Canidae.

Advantageously, the active compounds may be administered orally or parenterally. They may be administered orally in the form of a tablet, pill, capsule. bolus, which may vary from 50 mg. to 10 grams. or as a drench. liquid formulation or in the feed. When used parenterally. the compound is generally dissolved in a DETAlLED DESCRlPTlON The following examples describe in detail the preparation of compounds of this invention and the testing of representative compounds against helminths in warm-blooded animals.

EXAMPLE 1 Preparation of 3'-Bromacetylacetanilide (IA) To a stirred solution of 110.0 g. (0.62 mole) of 3'- acetylacetanilide in 2400 ml. of chloroform is added dropwise a solution of 33.0 ml. (102.9 g; 0.644 mole) of bromine in 240 ml. of chloroform. The solution is stirred 1 hour and the resultant precipitate is then filtered. washed with ether and dried. The solid is stirred in a large volume of water to give an oily precipitate which crystallizes on further stirring. The solid is filtered, washed with water and then 2-propanol. The dried product weighs 148.34 g., and is recrystallized from 2-propanol to give the product, melting point l08.5l 10C. Analysis: Calcd. for C H BrNO Calc: C, 46.90; H, 3.94; Br, 31.20; N, 5.47. Found: C. 47.12; H, 3.94; Br, 31.21; N, 5.47.

EXAMPLE 2 Preparation of 3'[(2-lmino-4-thiazolin-3- yl)acetyl]acetanilide hydrobromide (11A) A solution of 64.8 g. (0.253 mole) of 3'-bromoacetyl acetanilide (Example I) and 25.3 g. (0.253 mole) of Z-aminothiazole in 450 ml. of acetone is heated at 50-60C. for 2 hours. The precipitated product is filtered, washed with acetone and dried to give 58.74 g. of crude product which on recrystallization from methanol-ether gives the product melting point 225 dec. Anal. Calcd. for C,;,H, BrH O S: C, 43.83; H, 3.96; Br, 22.43; N, 11.80; S, 9.00. Found: C, 43.90; H, 4.21; Br, 22.21; N, 11.73; S, 8.69.

EXAMPLE 3 Preparation of 3 (2-lmino-3-thiazolidinyl )acetyl lacetanilide hydrobrornide (118) A solution of 5.12 g. (0.020 mole) of 3- bromoacetylacetanilide in 70 ml. of acetone is added to a stirred solution of 2.04 g. (0.020 mole) of 2-amino-2 thiazoline in 30 ml. of acetone. The mixture is stirred 1.5 hours and the precipitate then filtered, washed with acetone and dried to give 6.00 g. of white solid, which on recrystallization from water gives the product, melting point 275277C. Anal. Calcd. for C H BrN O S: C, 43.58; H, 4.50; Br, 2231; N, 11.73; S, 8.95. Found: C, 43.99; H. 4.66; Br, 22.51; N, 11.72; S. 9.14.

50C.. filtered. and the filtrate evaporated at reduced pressure. The residue is azeotroped with toluene, then triturated with 2-propanol and filtered to give 258 g. of crude product, which on recrystallization from aqueous acetic acid gives the product, melting point 224-226C. Anal. Calcd. for C,,-,H =,N O ,S: C. 56.77; H, 4.76; N, 13.24; S, 10.10. Found: C, 56.88; H, 4.77; N, 13.16; S, 9.90.

EXAMPLE Preparation of 3 2-[ 2-( acetylimino)-4-thiazolin-3-yl l- 1 hydroxyethylacetanilide hydrobromide (IVA) To a stirred mixture of 3.2 g. (0.01 mole) of 3'-[2- (acetylimino)-4-thiazolin-3-yl]acetyl acetanilide (Example 4) in 30 ml. of 95% ethanol is added 0.30 g. (0.0078 mole) of sodium borohydride. The mixture is stirred 2.5 hours, poured into water and acidified with acetic acid. The solution is evaporated under reduced pressure and the residue crystallized from dilute hydrobromic acid to give 2.25 g. of product, which on recrystallization from water gives the product, melting point 228C. dcc. Anal. Calcd. for C, H,,,BrN O S: C, 45.00; H. 4.53; Br, 19.96; N, 10.50; S, 8.01. Found: C, 45.11; H, 4.81; Br. 20.16; N, 10.57; S, 7.74.

EXAMPLE 6 Preparation of 3'-[ 1-Hydroxy-2-(2-imino3-thiazolidinyl)ethyl1 acetanilide hydrochloride (lVB) To a stirred slurry of 63.47 g. (0.177 mole) of 3'-[ (2- imino-3-thiazolidinyl )acetyl lacetanilide hydrobromide (Example 3) in 1 liter of 95% ethanol, maintained at 5C., is added 5.70 g. (0.15 mole) of sodium borohydride. After stirring 40 minutes an additional 4.10 g. of sodium borohydride is added and the mixture is aciditied with hydrochloric acid and evaporated under reduced pressure. The residue is partitioned between chloroform and dilute aqueous ammonium hydroxide. Two further chloroform extracts are combined with the original, washed with brine, dried (sodium sulfate) and evaporated to give an oil. Treatment with acetone gives 26.77 g. (48%) of white crystalline hydrochloride. which has melting point 235237C. Anal: Calcd. for C, -,H,,,ClN,,O S:x Calcd: C, 49.44; H, 5.74; CI, 11.23; N. 13.31; S, 10.15. Found: C, 49.87; H, 5.27; Cl, 11.51; N, 13.25; 5, 10.40.

EXAMPLE 7 Preparation of 3 5 ,o-Dihydroimidazol 2, l -b ]thiazol-6 -yl)acetanilide perchlorate (VA) To a stirred mixture of 6.00 g. (0.015 mole) of 3-2- {2( acetylimino )-4thiazolin-3-yl l -hydroxyethyl acetanilide hydrobromide (Example 5) in 90 ml. of dry DMF (dimethylformamide) is added dropwise, 2.0 g. (0.017 mole) of thionyl chloride. The mixture is stirred 2 hours at 50-55C. then cooled to 25C. and stirred while 1.17 g. (0.0099 mole) of thionyl chloride is added dropwise. The mixture is stirred 30 minutes at 25C. and then at 5055C. for 1 hour. The mixture is cooled, filtered, and the filtrate evaporated at reduced pressure. After refluxing the residue is 100 m1. of acetic anhydride for 1.5 hours, the acetic anhydride is distilled at reduced pressure. The residue is dissolved in dilute hydrochloric acid, filtered, made basic with cone. ammonium hydroxide and extracted twice with methylene chloride The combined organic layers are extracted with dilute hydrochloric acid and the product extracted with base back into methylene chloride. The dried methylene chloride solution is evaporated to give an oil which is converted to the perchlorate salt, which on recrystallization from 95% ethanol gives the product, melting point 185"l87C. Analysis: Calcd. for C,;,H CIN O =,S: Calcd: C, 43.39; H, 392; Cl, 9.85; N, 11.68; S, 8.91. Found: C, 43.37; H, 3.82; Cl, 9.90; N, 11.50; S, 8.82.

EXAMPLE 8 Preparation of 3'-( 2,3 ,5,6-Tetrahydroimidazo[ 2, 1 -b]thiazol-6- yl)acetanilide (VB) Addition of 5.00 g. (0.0158 mole) of 3'-[ l-hydroxy- 2-( 2-imino-3-thiazolidinyl )ethyllacetanilide hydrochloride (Example 6) to 15 m1. of concentrated sulfuric acid is carried out in small increments over 0.5 hour. The orange solution is stirred an additional 1 hour, poured onto ice and made basic with concentrated ammonium hydroxide. The aqueous base is extracted twice with chloroform and the combined organic layers washed with water, brine, dried (sodium sulfate) and evaporated at reduced pressure to give 3.76 g. of an oil. Crystallization from ether gives 3.32 g. crude yield) of fine white crystals, which on recrystallization from 2-propanol gives the product melting point 164166C. Analysis: Calcd. for C l-l N OS: Calcd: C, 59.74; H, 5.79; N, 16.08; S, 12.27. Found: C, 59.93; H. 5.85; N, 15.96; S, 12.49.

EXAMPLE 9 Preparation of 6-( m-Aminophenyl )-5 ,6-dihydroimidazo[ 2, 1 b ]thiazo1e dihydrochloride (VllA) A 2.80 g. (0.0078 mole) portion of 3'-(5,6- dihydroimidazo[2,1blthiazol-yl)acetanilide per chlorate (Example 7) is converted to the free base and then dissolved in 15 ml. of 6N hydrochloric acid. The solution is stirred at reflux for l .6 hours and then evaporated at reduced pressure. The residue is azeotroped with 2-propanol and crystallized from ethanol/-2- propanol to give 1.69 g. (75%) of crystalline product, melting point 242244C. Anal. Calcd. for C H Cl N S: C, 45.54; H, 4.52; C1, 24.43; N, 14.48; S, 11.05 Found: C, 45.39; H, 4.66; Cl, 24.26; N, 12.27; S, 10.83.

EXAMPLE 10 Preparation of 6-( m-Aminophenyl)-2.3,5,6-tetrahydroimidazo[2.1-

b]thiazole Dihydrochloride (VllB) A solution of 1.00 g. (0.0038 mole) of 3'-(2,3,5,6- tetrahydroimidazo[ 2, l -b lthiazol-o-yl )acetanilide (Ex ample 8) in 17 ml. of 6N hydrochloric acid is heated at reflux for 2.5 hours and then allowed to stand overnight at room temperature. The solution is concentrated at reduced pressure, made basic with concentrated aque ous sodium hydroxide while cooling and then extracted with 3 portions of chloroform. The combined organic layers are washed with brine, dried (sodium sulfate) and evaporated to give 0.84 g. of an oil, i.e., maminotetramisole free base. The oil is dissolved in hot methanol and strongly acidified with hydrogen chloride in 2-propanol. Evaporation of the solution and crystallization of the residue from lpropanol gives 0.91 g. (81%) of cream colored solid. melting point l98201C.. dec.

EXAMPLE 1 1 Preparation of 6-(m-Aminophenyl)-2,3.5.o-tetrahydroimidazol2,1-

b]thiazole Dihydrochloride (VllB) To a stirred slurry of 22.57 g. (0.10 mole) of stannous chloride dlhydrate in 35 ml. of conc. hydrochloric acid. cooled to C. is added 7.14 g. (0.025 mole) of 6-( m-nitrophenyl )-2.3 ,5.6-tetrahydroimidazo( 2. l b]thiazole hydrochloride in one portionv The reaction is allowed to proceed to 40C. for 30 minutes and then heated to 7580C. for 3 hours. After pouring onto ice. the mixture is neutralized with aqueous sodium hydroxide and extracted into methylene chloride. The methylene chloride solution is washed with water. dried (magnesium sulfate) and evaporated at reduced pressure to give the free base as a yellow oil. The free base is dissolved in methanol and treated with excess 2- propanol-hydrogen chloride. Evaporation of the solvent and treatment of the oil residue with acetonitrile gives 5.08 g. (68% yield) of crude product which is recrystallized from 95% ethanol to give the white product. melting point 202-205C. Anal. Calcd. for C l-l N SCl C. 45.21; H. 5.17; N, 14.38; S. 10.97; C1. 24.27. Found: C, 44.80; H. 5.60; N. 14.08; S. 11.07; Cl, 24.07.

EXAMPLE 12 Preparation of 3'-(2,3.5,6-Tetrahydroimidazo[2, 1-b-]thiazo1-6-yl)- formanilide (VllIA) Method A A mixture of 3.29 g. (0.015 mole) of 6-(maminophenyl)'2,3.5.6-tetrahydroimidazo[2.lblthiazole free base. (obtained by basification of the dihydrochloride salt). 5 g. of 90% formic acid and 45 ml. of toluene is stirred in an oil bath while maintaining a very slow distillation. The initial distillate containing water distilled at 7692C. The temperature rises to 105C. After two more distillations with 45 ml. of toluene and 5 g. of 90% formic acid. the total reaction is 4 hours. The residue is partitioned between aqueous potassium carbonate and chloroform. The aqueous layer is extracted with chloroform and the combined organic layers washed with water. dried (magnesium sulfate). and the solvent evaporated at reduced pressure to give a white solid. Trituration with acetonitrile and recrystallization from ethanol gives the product. melting point l77l 79C.

Method B A solution of 14.5 g. (0.0664 mole) of the free base is dissolved in 75 ml. of 971()()% formic acid and the solution heated in the steam bath 2 hours. The excess formic acid is distilled on a rotary evaporator at reduced pressure. The syrupy residue is dissolved in water. Some methylene chloride and cracked ice is added and the two-phase system stirred and basified with potassium carbonate solution. The bulk of the product crystallizes and is insoluble in either phase. This fraction is recovered by filtration. washed with water fol lowed by acetonitrile. A small amount is obtained by evaporation of the dried (potassium carbonate) methylene chloride phase bringing the total yield to 1 l 15 g. (0.045 mole). 60%; melting point 176l78C.

EXAMPLE 13 Preparation of 2.3.5.6-Tetrahydro-6-(mmethylaminophenyl)imidazo[2.1-blthiazole Dihydrochloride (lXA) To a stirred slurry of 1.15 g. (0.030 mole) of lithium aluminum hydride in ml. of dry tetrahydrofuran is added 5.00 g. (0.0203 mole) of 3'-(2.3.5.6- tetrahydroimidazo[2.1-b]thiazol-6-yl)formanilide (Example 12) at a rate sufficient to keep the temperature at 40-45C. The reaction mixture is then stirred at room temperature for 3 hours and at 4050C. for 30 minutes. After cooling the reaction, 1.8 m1. of water is cautiously added dropwise and then 2 m1. of 15% aqueous sodium hydroxide. The mixture is filtered and the filter cake washed with tetrahydrofuran. Evaporation of the solvent gives an oil which is dissolved in methanol and acidified with 2-propanolic hydrogen chloride. Filtration of the precipitate gives 4.] 8 g. (67% yield) of crude product which is recrystallized from methanol and has melting point 22923|C. Anal. Calcd. for C, H,,.N SCl: C, 47.06; H. 5.60; N. 13.72; S. 10.47; C1. 23.15. Found: C. 46.82; H. 5.56; N. 13.60; S. 10.40; Cl. 23.16.

EXAMPLE 14 Preparation of l-2.3.5.6-Tetrahydro-6-(m-nitrophenyl)imidazo[2.1' b]thiazole d-tartrate (VIA) Procedure A A 28.58 g. (0.10 mole) portion of the dl6-(mnitrophenyl)-2.3.5.6tetrahydroimidazo[2.1-blthiazole hydrochloride is converted to the free base. A mixture of the free base, 15.0 1 g (0.10 mole) of d-tartaric acid in 520 ml. of 95% ethanol is heated on the steam bath and then allowed to cool to 30C. The precipitated salt is filtered. washed with ethanol and dried to give 15.4 g. (77%) of the l-base. d-acid salt. melting point l81182C.. dec.. [a1,,58.1 (C 7.7. H 0). Two recrystallizations from ethanol give the analytical sample. melting point 182C.. dec.. [od -603 (c 7.5. H 0).

Procedure B To a solution of 0.05 mole of d. l -6-(m-nitrophenyl 2.3.5.o-tetrahydroimidazol2.l-b]thiazole free base (prepared from 14.30 g. (0.050 mole) of the corresponding hydrochloride) in 200 m1. of hot ethanol was added 3.75 g. (0.025 mole) of d-tartaric acid in one portion. The mixture is refluxed briefly and then allowed to cool to room temperature. The precipitate is filtered. washed with absolute ethanol and dried to give 7.95 g. (79.7%) of the l-base, d-acid salt. melting point 184C. [a],,56.2 (c 6.8. H 0).

EXAMPLE l5 lsolation of l-6-( m-Nitrophenyl )-2.3,5 .6tetrahydroimidazo[ 2. l blthiazole hydrochloride (VlB) Conversion of 10.4 g. of l-base. d-tartrate salt to the free base and treatment of an ethanolic solution of the free base with 2-propanol-hydrogen chloride gives 7.05 g. of l-6-( m-nitrophenyl )-2.3.5 .6-

19 tetrahydroimidazo[2,1-b]thiazo1e hydrochloride, melting point 209210C., [01],, 96.9 (c 6.7, H 0). Two recrystallizations from ethanol gives the essentially pure product with [01],, 99.4 (c (1.4, H 0).

EXAMPLE 16 Preparation of l-6-( m-Aminophenyl )-2,3,5 ,6- tetrahydroimidazo[ 2, 1 b]thiazo1e Dihydrochloride (VllC) Cl, 24.27. Found: C, 45.23; H, 5.19; N, 14.34; S,

EXAMPLE [7 Preparation of d-2,3,5 ,6-Tetrahydro-6-( maminophenyl)imidazo[ 2,1 -b]thiazo1e Dihydrochloride VllD) EXAMPLE 18 Preparation of I( )6-( m-lsobutrylaminophenyl )-2.3,5 ,6- tetrahydroimidazo[2, l -b]thiazole dibenzoyl l-(+) tartrate A solution of 2.9 g. (0.01 mole) of 6-mm isobutrylaminophenyl )-2,3,5 ,fi-tetrahydroimidazol 2. l

bjthiazole in 15 ml. of hot methanol is added to a solution of 3.8 g. (01 mole) of dibenzoyl-d-tartaric acid in 25 ml. methanol. The salt which crystallizes on cooling is recovered by filtration. The yield is 2.7 g. 83% of the l() amine, melting point l83.5l 845C. Recrystallization gives a product melting point l82-183C. [01],,

75.6 (C=1.37 dimethylsulfoxide).

The other isomer of the amine is obtained by employing the optically active dibenzoyl tartaric acid.

EXAMPLE 19 Using the same procedure described in the Example 18 above, the acetamide and benzamido analogs are resolved. These resolved salts can be acid hydrolyzed to obtain the amino derivative by methods well known for hydrolyzing amides. They can also be converted to the base form of the imidazo[2,l-b]thiazole by treatment of the tartrate salts with ammonium hydroxide or other base. The physical properties of some of the resolved salts are listed in the table below.

TABLE I N S Dibenzoyl-d-tartrate salts l c9211 i-icocql gcooch' coax Calculated Found Melting solgent Specific Recryst. Rotation Empirical Formula c H N S c H N s R Degree C. (u) %b i 125.0 CH: 1515-15 15 MeOli (C=l.60,Me0H) N3S0C13H15-08C18H19 60.0 1.72 6.78 5. 59. 5 .7 7 3 5.7

r 45. 6" NHC0CH(CH3)2 182-18:- MeOH c=1.3'r nmso) nssocunt c a 61. 19 5.1 1 6. 19 1.95 60.77 5. 1 5' 5- 5 1 rm co-G 20 i 207 (c 0.90.DMs0} 500 11 0 0 14 65. 12 4.58 6.16 4.70 63.25 1.6} 6 65 5 5 The procedure described in Example 16 is followed. 61)

EXAMPLE 20 Preparation of 6-( m-isopropylaminophenyl )-2 ,3 .5 ,6- tetrahydroimidazol2,1-b1thiazole 5.0 g. (0.023 mole) of the free base of imidazo[2,lblthiazole 2.3.5,6-tetrahydro-6-(m-aminophenyl)dihydrochloride (m-aminotetramisole) is dissolved in a mixture of 40 m1. ofmethanol and 20 ml. of l N sodium acetate water solution. The pH of the solution is adjustcd to h--7 (slightly acid) with addition ofacetic acid (2 ml.) and the solution is then added to 8.5 g. (.05 mole of 2-iodopropane. The mixture is refluxed for 48 hours. After cooling, the excess 2-iodopropane and methanol is evaporated on the rotary evaporator. The residue is then partitioned between 100 ml. chloroform and 50 ml. water. With stirring and cooling, the system is made basic (pH by the addition of sodium hydroxide solution. The chloroform layer is removed, and the aqueous layer is washed with (2 X 75 ml. portions) of chloroform. The chloroform extracts are dried over magnesium sulfate and the chloroform evaporated to yield a white solid. melting point 475 I C. The isopropylated product is then dissolved in 150 ml. acetone and a solution of hydrogen chloride-acetone is added. The hydrochloride salt as an acetone solvate precipitates from the solution. The salt is filtered to yield 2.2 g. (0.056 mole. 25% yield) of a white solid. melting point 80l70C. Calcd. C, 42.83; H, 5.40; N, 10.71; S. 8.17; CI. 18.07. Found: C, 43.78; 43.89; H, 5.55; 5.79; N, 10.85; S, 8.47; C1, 1829.

EXAMPLE 2] Preparation of 6-1m-( isopropylmethylamino )phenyl ]-2,3,5,6- tetrahydroimidazo[ 2. l -b lthiazole The above compound is prepared in a manner similar to Example 1 by alkylating 3'-N-methyl-maminotetramisole with 2-iodopropane in a watermethanol solution. The product which is very hydroscopic has infrared and nmr spectra consistent with what was expected for the product.

EXAMPLE 22 Preparation of N-isopropyl-3 2,3 ,5 ,6-tetrahydroimidazo[ 2, l b]thiazol-6-yl) formanilide dihyclrochloride To 4.0 g. (0.015 mole) of the 3-Nisopropyl-maminotetramisole derivative, Example 18, is added 25 ml. of formylacetic anhydride. The mixture is heated on a steam bath overnight 14 hours). The excess anhydride is then removed under reduced pressure and the residue is taken up in 50 m1. ofchloroform. The chloroform solution is washed (3 X 75 ml.) with water. The water washings are combined and 100 ml. chloroform is added. The mixture is made basic (pH 10) with sodium hydroxide solution and the chloroform layer separated. The aqueous layer is extracted with 2 X 100 ml.

2.6 g. of a thick oil. The formylated product is purified by column chromatography (silica gel. chloroform and 10% methanol/CHCl used as elutants). The hydrochloride salt is prepared by dissolving the free base in chloroform and bubbling in gaseous hydrogen chloride. The salt did not precipitate and therefore the salt is isolated by removing the chloroform under reduced pres sure. The crystalline, white solid, melting point 70C. is found to be very hygroscopic. Calcd. C, 47.37; H, 6.10; N, 11.04; S, 8.43; C1, 18.64. Found: C, 47.76; H, 4.98; N, 10.68; S, 8.14; Cl, 17.32.

EXAMPLE 23 Preparation of 3 2 ,3,5,6-tetrahydroimidazo[ 2, l -b lthiazol- 6-yl )isobutyranilide hydrochloride 2.2 G. (0.010 mole) of m-aminotetramisole is dissolved in a mixture of 15 ml. methanol and 15 ml. water and the pH is adjusted to about 6 with an aqueous hydrochloric acid solution. This solution is then added to 3.2 g. (0.020 mole) of isobutyric anhydride. The mixture is allowed to stand at room temperature for 12 hours. The reaction mixture is then added to a mixture of ml. methylene chloride and 50 ml. water and then made basic (pH 10) with an aqueous sodium hydroxide. The methylene chloride layer is removed and the water layer is washed twice with 75 ml. of fresh methylene chloride. The methylene chloride extracts are then combined, dried over magnesium sulfate. and the methylene chloride evaporated leaving a tacky solid. The free base of the product is recrystallized from a chloroformethyl ether mixture. The yield is 1.6 g. (55%). The hydrochloride salt is prepared by dissolving the free base in methanol and adding an excess of hydrogen chloride gas. The methanol is then removed on the rotary evaporator to yield a glassy white solid, melting point 125140C. Calcd. C, 52.39; H, 6.45; N. 12.22; S, 9.32; CI, 10.31. Found: C, 52.40; H. 6.25; N, 12.32; S. 9.46; Cl, 10.57.

EXAMPLES 24-30 Following the procedure of Example 21 and reacting dlor l-meta-aminotetramisole with the proper acid chloride or anhydride, compounds of the following portions of additional chloroform. The chloroform ex- N tracts are combined, dried over magnesium sulfate and 1 the solvent removed under reduced pressure to yield R R1 Melting Melting point Analysis Analysis NRRL, X point free base calculated found HN(.O (H (H, d1 HCl 121M311 121x122 50.97 t 5 1.11: H. Sulultc H 6.1 l H 6.112 N 12.74 N 13.011 :4 s 1.73 s ans (1 111.75 (1 mus HN('()-(ll. .CH- .(H. 11(1 112 123 12 52.39 t 53.44 d1 H. Sohatc H (1.45 H (1.37 N 12.22 N 12.36 25 S 1.32 S 9.21 (1 111.31 (1 111.41 HNC()(HI('HJ1Q Ht'l 131) 111 H2O Suhatu EXAMPLES 31-32 Preparation of 3 5.6-Dihydroimidazol 2. l -b lthiazolo-yhpivalanilide and 3 5.6-dihydroimidazol 2. l -b ]-o-yl )-isobutyranilide To a stirred solution of 2.0 g. (0.007 mole) of 6-(maminophenyl1-5.6-dihydroimidazo12.l-b]thiazole dihydrochloride in 50 ml. of 50% aqueous methanol is added aqueous sodium hydroxide to give pH 6. Pi valic anhydride is added and the solution is stirred overnight at room temperature. Chloroform is added and the pH is adjusted to 9-10 with aqueous sodium hy droxide. The organic layer is separated and evaporated to dryness. The residue is slurried with ether and fil tered to give 1.6 g. crude product. Recrystallization from ethyl acetate gives 0.75 g. of 3'-(5.6- dihydroimidazoI 2. l -b]thiazol-6-yl )pivalanilide. melting point 163l65C.

By the above procedure 3'(5.o-dihydroimidazo[2.l b]thia2ol-6-yl)isobutyranilide. melting point l75l78C. is obtained when isobutyric anhydride is used in place of pivalic anhydride.

EXAMPLE 33 Preparation of dl-m-( 2.3.5.fi-tetrahydroimidazol 2. l -b lthiazolo-yl)carbanilic acid methyl ester. hydrochloride To 2.6 g. (0.009 mole) of the dihydrochloride of dlm-aminotetramisole (Example 10) is added 40 ml. of a 1.0 m-sodium acetate buffer. The solution (pH 4.6) is cooled in an ice bath and then 3.0 gv (0.032 mole) of methyl chloroform-ate is added. (2 molar excess) and the solution stirred for minutes. After an additional 15 minutes at room temperature. the solution is then cooled in an ice bath and 50 ml. methylene chloride is added. The mixture is made basic with an aqueous so dium hydroxide solution (pH 10).

The methylene chloride layer is separated and the water washed (2 X 50 ml.) with additional methylene chloride. The methylene chloride washings are com bined. dried over magnesium sulfate and on removal of the solvent. 1.4 g. (50% crude yield) of product as the free base is isolated. After being recrystallized from ethyl acetate the free base has a melting point of 135138C. The free base is converted to the hydrochloride salt by dissolving the recrystallized free base in acetone and passing dry hydrogen chloride gas through the solution. The hydrochloride salt precipitates and is recrystallized from ethanol; melting point 245 24oC Anal. C. 49.75: H. 5.14; N. 13.39; S.

10.22; C]. 11.30. Found: C. 49.72; H. 5.30: N. 13.10; S. 9.93; C]. 11.02.

EXAMPLE 34 Preparation of 1-m-( 2.3.5 .6-tetrahydroimidazo[ 2. l-b ]thiazol- 6-yl)carbanilic acid methyl ester. hydrochloride Following the procedure of Example 33 and substituting l-mmminotetramisole for dl-m-aminotetramisole the above compound is obtained having a melting point of 239-240C. The analysis of the compound is as follows: Anal. C. 49.75; H. 5.14; N. 13.39; S. 10.22; Cl. 11.30. Found: C. 49.65: H. 5.21; N. 13.20; S. 10.05: Cl. 1 1.40.

EXAMPLE 35 Preparation of l-6-(5-amino-2-nitrophenyl)-2.3,5.6- tetrahydr0imidazo[ 2. l -b lthiazole. hydrochloride. acetone solvate 4.3 g. (0.014 mole) of the nitrate salt ofl-NacetyLmaminotetramisole is cooled in an acetone-dry ice bath and then 50 ml. of concentrated sulfuric acid is added. The salt dissolves in the sulfuric acid and the solution is allowed to stand at room temperature for 5 days. The mixture is then poured over 200 g. of ice and 300 ml. of chloroform is added. With cooling in an acetone-dry ice bath. the acid is neutralized with concentrated ammonium hydroxide and the pH is adjusted to about 10. The chloroform layer is separated and the water layer washed with an additional 150 ml. chloroform. The chloroform extracts are combined. washed with water. dried over magnesium sulfate and the solvent evaporated on a rotary evaporator to yield 3.3 g. of a yellow solid. The yellow solid is then heated in 50 ml. 6 N hydrochloric acid in a steam bath for 3 hours in order to hydrolyze the acetyl group. After cooling. 200 ml. chloroform is added and the acid neutralized with concentrated ammonium hydroxide. The pH is adjusted to 10 and the chloroform layer removed. The water layer is washed twice with an additional ml. chloroform. Then the chloroform washings are combined. dried over magnesium sulfate. and the solvent removed to yield 1.5 g. of a yellow solid. The nitro compound is recrystallized from chloroform and dried; melting point 228-229C. (dee). The free base is converted to the hydrochloride salt by dissolving the free base in acetone and then a saturated hydrogen chlorideacetone solution is added. The hydrochloride salt precipitates out and is filtered and dried; melting point l402 10C. The salt could not be readily recrystallized. Analv C.

25 46.74; H. 5.2l; N. 15.58; S. 8.92: CI. 9.86. Found: C. 45.20; H. 4.99; N. 15.68;S.9.()81Cl. 11.79.

26 talli/cd from ethanol and dried; melting point l7()*2l(l( (dcc). (alcd (I 35.60; H. 4.02; N. H32; S. 8.64. Found: C. 36.94; H. 4.02; N. l().75; S.

EXAMPLE 36 Preparation of 8-17 dl-b-(4-bromo-3-nitrophenyl)-2.3.5.6- EXAMPLE 38 tetrahydroimidzwoi 2,1 -b]thiazole. hydrochloride Preparation oi On the nitration of 4-hromotetramisole (6-(4- 5 i -Z-bromophenyI)-'.Z,3.5.6- brornophenyl )-2,3.5.dtetrahydroimidazol 2. l x m tetrahydroimidazo[ 2, l -blthiazole b]thiazole) recovering the nitrated product as the tree base and acidifying with hydrogen chloride. the above Following the procedure of Example 35 and substicompound is obtained having a melting point of tutirig l-acctylaminotetramisole for dl-m- Analysis Culcdfol'i 3523; aminotetramisole the above compound is obtained havl [-533 879; 21-91 Found: 3597; 2-95; H ing as the base a melting point of l95l97C. On anal- L40; '5 2209' ysis the product had the following values: C. 45.89; H, g' f g s g gg 4.15; N, 12.35; s. 9.43; Br. 2349; Found: c, 46. l5; H.

3.85; N, I250; S. 9.45: Br. 23.82. bromophenyl )-2,3,5 ,6-tetrahydroim|dazo[ 2. l b]thiazole is obtained as the free base having a melting 3 EXAMPLE 39 point of 129-l3()C. Preparation of EXAMPLE 37 l-6(S-amino-Z-bromophenyl)-2,3,5,(1

. tetrahydroimidazol 2, l -bjthiazole Preparation of dl-6-(5-amino-2-bromophenyl)-2,3,5.()- Following the procedure of Example and substitetrahydroimidazo[2 l-b]thiazole, dihydrochloride Hing lm'aminotctwmisole for dl'mamlnotetmmisole o 33 g (0.015 e) of dl m umino tetmmisole is the iiboveoproduct is obtained having a melting point of I75 I77 C. An analytical sample on analysis shows added 4t) ml. of concentrated sulfuric acid along with w Calculated C 4430: H. 4.06; 1404; S. 0'75; Br 2.5 g. silver sulfate. The miitture is warmed on the 26.80 Found: C 44-10; H, 4.02; N, 396; S 0.75; steam bath to get the solids in solution. Then 2.7 g. Br 2658- (O.[)l7 mole) of bromine is added slowly to the warm solution and there is an immediate formation of a white EXAMPLES 46 precipitate. The reaction mixture is stirred at room 35 General method of ucylution of temperature for 12 hours and then is poured over about (H mflminophenyl 23.5bmtmhydmimidazol l I00 g. of ice. The silver bromide precipitate is filtered bhhiazole and off, the sulfuric acid solution is cooled in an ice bath. i h l 5 dih d i id 2 1 150 ml. of chloroform is added. and the acidic solution blthiazole to prepare the amide or the carbamate is then carefully neutralized with concentrated ammo- 40 function nium hydroxide- The P is raised 10 about Chlo- A solution of the amino derivative in an aqueous sysroform layer is separated. and the water layer washe tem is treated with at least one molar equivalent of a twice with an additional 75 ml. chloroform. The Chlocarboxylic acid halide or anhydride or alkoxycarbamroform washings are dried over magnesium sulfate and 0y] Chloride at a P Suitable for amide formation at the the solvent removed on the rotary evaporator to yield amino gnfmp P favorable for ucylatio at an off-white solid. which is recrystallized from chlorom the lmldazo After the fmhydnde 9 chloride has reacted the reaction mixture is made basic form. The brominated product has a melting point of l53]56C. The h drochl ride s' it is re ared b di-- wh'ch i hydrolyzes Dilly groups from y 0 d p p y 5 the 7-position leaving only the desired compounds. Desolvmg the free base in acetone and adding hydrogen tails for specific compounds are listed in Examples 2 l, chloride gas. The white salt precipitates out and is fil- 23 29 30 31 and 32 Using these procgdures h f ltered and dried; 2.6 g. (47% yield). The salt is recryslowing are prepared.

Starting Acylfating Product MLLQ Agent Chloride or M N @qm "H2 R -Continued (a|k \luminophcn \l)-5 |-(.|il'\}dr l and 23.5.6- Starting Acylatin Product tctruhydroimidumlll-hlthiu/oles Prepurutirms of M CETial Aient these compounds are outlined below Chloride or Anhvdride g Alkyla'oinr' [went Product C e X- r ,O- K A r g- H :1 LI It i H l olefimc R C C C H g s S H H ll C=C=C LL C x (Cl-l:) CO X (c.-.2) n

CONH- l to 6 Y Y i l H p) n 51 CH2 CH2 X CH2. Chanr-X 5 35 t,.-.- 5 Heterocyrlic He. ero- H O c min ((3.2 n (CH2)n I: Q C- u te r: etclic EXAMPLE 9; H 0 Preparation of I 6-[m-lFurfuryluminolphenyll-llS.6- W C tetruhydroimidaztd l l -h lthinzole O A mi\ture of 44 g (0.020 mole) of 6-mh 5 .iminophenyll-Z 3.5.o-tetrnhydroimidrizol2.1- +6 Alkoxy C- L blthiuzole. ll g, [0.021 mole) furfurul. 3,5 m]. acetic C H LlCiLl and ml. methanol are placed in d reuetion flask C 5 along ith some molecular sieves, To this 003 g. will a a molel of sodium oumohorohydride is added slmxl} and L the mixture stirred 1 hours. The mixture is now ueidilied to pH 1 with h droehloric ueid. A solid material is V 1 remo\ ed by triturution and the sohent evaporated EXAMPLES 4 leaving an oil residue The following is a general method for rilk luting o The oil is partitioned between dilute HCl rind ehloro- (m-;iminophenyll-Z.3.5.o-tetmhydroimidnlol 2. I- form The aqueous la er is separated and fresh chlorohlthiu/ole and o-tnruminophem l5.( form is added The t\\ 0 phase mixture is made alkaline dihydroimidu/olll-l lthiuiolel The procedure outwith Ammonium h \dro\ide and the chloroform ltrxer lined in Example 18 is used to prepare other sepurated.driedamde\;ipor;ited.The Uih'produfl er talli/cs from ether to \ield 4.1 g. ((19% The product has a melting point 99.5|0I(. after recrystallization from an ctl1 \'l acctate-hcplane mixture. Anal. Calcd.

Starting Hateria 1 for C,.;H,;N SO: C. 64.19; H. 5.72; N, 14.03; S, 10.71. Found: C, 64.47; H. 5.67; N, 14.20; S, 11.04.

EXAMPLE 54 Following the procedure outlined in the previous Example 53 and substituting the appropriate aldehyde or ketone. the following compounds are prepared:

are prepared by the procedures described in the chemical literature. Compounds prepared by this procedure are illustrated below:

represents a basic function, that is a primary. secondary pea % Calculated I5 Found I Melting Solvent 0! linpir'icul C H N s C i N 3 1t )3 Yield lnint linen st. Formula :.1( :,1 "1,011 7 165-170" 011,01, 1|, SUC i1 60.62 6.90 15.15 11.56 1 60. 11 6.7 1 1.89 11.5? I l i .r '1 1 .7-1 .1? 1.r. A.-- 11,:1c ii 7 67.7 1 7.69 15. 1 1 111. 5. lrilalu 7, 16 1 lk.')j

L/ he; t. inc 7 2 ,x s (.9 9).3-101" 1.111s- 15100 51 01.17 5.3: 1 1.0 u1.'/1 1. .6. 1 1..e 11.01

l .l lie-tine 7 l 15 li o-116 1-.mAr- 1531: 11 69.8? 6.1 13.58 10.56 711.09 5.65 15A) 10.,u

.:: llf'pl.ltl9

7 1 )cjil, 130 11 1-118 lat Ac- "1 67.23 6.9 1 12, m 67.10 5,39 1350 9,56

"- heytcuu:

11.-. 65 107-110 EwAC- a se a 65.78 5.8M 18.05 10.5) 65.70 5.80 18.26 10.2)

. hept'ine EXAMPLES 55l 12 The following are two general methods which are used for preparing the fi-(suhstituted phenyll-Zfifibtetrahydroimidazol2.1-hlthiaxoles and 6-( substituted phenylJ5,(1-dihydroimida/o[2.1-l1lthiazolcs shown in Table ll.

A. Following the procedures outlined in Examples 1, 2. 3, 4, 5. (1, 7 and 8, a series of substituted compounds are prepared from substituted acetophenconcs which of tertiary amine, the starting aminoacetopheneone is utilized as its hydrochloride or hydrohromide salt in the Example 1 reaction with hromine to form the whromoacctylaniline.

B. Following the procedures outlined in Examples 20. 21. 23, 3 l, 32 and 33, dlor l-m-aminotetramisole is either alkylated with the appropriate alkyl. aralkyl, or hctcrocyclicalkyl halide or acylated with the appropriate acid chloride or acid anhydride.

TABLE II continued OCIL;

Q-crwu a Br Brh-pyriundinyl TABLE l1 ccntinue d l 1 l l ll 0 4n;-

9 102 u C 1l ZllIC- E? 103 (cm mlcn c- H S? 4 cll gnmi c- H out,

2 105 (CH, rmcn H 107 ashme- 3 108 CH3NHC- a S 109 H NC- H 110 H U c U 9 111 ll I ll 9 112 H cmrc EXAMPLE I13 Preparation of lmidazo[ 2. l -b]thiazole, 6-(m-dimethylaminophenyl)-2.3,5,G-tetrahydrodihydrochloride A quantity of 6.0 g. mmol) of thionyl chloride is slowly added to 6.0 g. 18 mmol) of 3-[ l-hydroxy-2- (2-imino-3-thiazolidinyl)ethyl]dimethylanilidc hydrochloride in 100 ml. chloroform and the reaction mixture is stirred for l hour at room temperature. Then 200 ml. of water is added to the reaction mixture and the pH of the solution is adjusted to 9-l0 with potassium carbonate. The two phase system is refluxed for 8 hours The chloroform layer is separated, dried over magnesium sulfate and on removal of the solvent. 2.2

R R i l II H H ll

ll H

g. of a dark oil is isolated. The free base is then dissolved on acetone, acidified with hydrogen chloride and the product precipitated out. The dihydrochloride salt is filtered and dried. Yield 1.3 g. Melting point ]7()-200C. The product could not be purified by recrystallization from the usual sllvents. Structure is based on a comparison of IR and NMR spectra of the compound to closely related compounds.

EXAMPLES 114-173 Following the procedures hereinbefore described the 6-( meta-aminophenyl )-l ,Z.3,4-tetrahydr0 and 5.6 dihydroimidazo[ 2, l-h]thiazoles are prepared and identified. 

1. A METHOD FOR CONTROLLING GASTROINTESTINAL NEMATODES IN WARM-BLOODED ANIMALS COMPRISING ADMINISTERING TO SAID ANIMALS, A NEMATOCIDALLY EFFECTIVE AMOUNT OF A COMPOUND OF THE FORMULA:
 2. A method according to claim 1, wherein the said compounds are of the formula:
 3. A method according to claim 1, wherein the said compound is of the formula:
 4. A method according to claim 1, wherein said compound is administered orally at from 1 to 10 mg./kg. of body weight of said animal.
 5. A method according to claim 1, wherein said compound is administered parenterally at from 1 to 10 mg./kg. of body weight.
 6. A method according to claim 1, wherein the said compound is 6-(m-isobutyrylaminophenyl)-2,3,5,6-tetrahydroimidazo(2,1-b)thiazole.
 7. A method according to claim 1, wherein the said compound is 6-(m-benzoylaminophenyl)-2,3,5,6-tetrahydroimidazo( 2,1-b)thiazole.
 8. A method according to claim 1, wherein the said compound is l-6-(m-benzoylaminophenyl)-2,3,5,6-tetrahydroimidazo(2,1-b)thiazole hydrochloride.
 9. A method according to claim 1, wherein the said compound is 6-(m-pivaloylaminophenyl)-2,3,5,6-tetrahydroimidazo( 2,1-b)thiaZole.
 10. A method according to claim 1, wherein the said compound is l-6-(5-acetylamino-2-bromophenyl)-2,3,5,6-tetrahydroimidazo(2,1-b)thiazole.
 11. A method according to claim 1, wherein the said compound is 6-(m-(p-chlorobenzoyl)aminophenyl)-2,3,5,6-tetrahydroimidazo(2,1-b)thiazole.
 12. A method according to claim 1, wherein the said compound is 6-(m-formylaminophenyl)-2,3,5,6-tetrahydroimidazo(2,1-b)thiazole.
 13. A method according to claim 1, wherein the said compound is a 6-(m-loweralkanoylaminophenyl)-2,3,5,6-tetrahydroimidazo(2,1-b)thiazole. 